Effects of Chronic Undernutrition on Glucose Uptake and Glucose Transporter Proteins in Rat Heart

Abstract

The high energy demands of myocardium are met through the metabolism of lipids and glucose. Importantly, enhanced glucose utilization rates are crucial adaptations of the cardiac cell to some pathological conditions, such as hypertrophy and ischemia, but the effects of undernutrition on heart glucose metabolism are unknown. Our previous studies have shown that undernutrition increases insulin-induced glucose uptake by skeletal muscle. Consequently, we considered the possibility of a similar adaptation in the heart. With this aim, undernourished rats both in the basal state and after euglycemic hyperinsulinemic clamps were used to determine the following parameters in myocardium: glucose uptake, glucose transporter (GLUT) content, and some key components of the insulin signaling cascade. Heart membranes were prepared by subcellular fractionation in sucrose gradients. Although GLUT-4, GLUT-1, and GLUT-3 proteins and GLUT-4/1 mRNAs were reduced by undernutrition, basal and insulin-stimulated 2-deoxyglucose uptake were significantly enhanced. Phosphoinositol 3-kinase activity remained greater than control values in both conditions. The abundance of p85alpha and p85beta regulatory subunits of phosphoinositol 3-kinase was increased as was phospho-Akt during hyperinsulinemia. These changes seem to improve the insulin stimulus of GLUT-1 translocation, as its content was increased at the surface membrane. Such adaptations associated with undernutrition must be crucial to improvement of cardiac glucose uptake.

GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring

“…Studies involving severe and prolonged nutrient restriction (calorie or protein restriction) that either spans the entire gestation and postnatal period (8, 34 -38) or the late intrauterine and postnatal life until adulthood (day 70) have demonstrated changes in total and subcellular levels of skeletal muscle and myocardial GLUT4 reflecting enhanced insulin sensitivity (1,10,13). These changes are similar to the increased insulin sensitivity of the nutrient-restricted adult (1,8,9).…”

“…In addition, various investigators have examined the liver, skeletal muscle, and white adipose tissue (WAT), attempting to unravel the insulin receptor and its signaling system (10,17,34,35,37), the growth hormone-IGF system (59,60), and the insulin-responsive glucose transporter (GLUT4) (1,10,13,21,38) as possible mechanisms underlying the development of type 2 diabetes mellitus. In the adult type 2 diabetic human and animals, aberrations in the expression and/or translocation of the GLUT4 glucose transporter isoform have been observed to cause insulin resistance that is characteristic of this condition (18,30,46).…”

“…In contrast, neonatal and adult nutrient restriction in animals increases insulin sensitivity by increasing GLUT4 gene expression and protein concentrations (9,10). The intrauterine nutrient-restricted adult offspring expresses heterogeneity in perturbations, lending to some controversy (1,13,34,37). We therefore hypothesized that intrauterine nutrient restriction negatively affects GLUT4 gene expression and subcellular distribution in a tissue-specific manner, whereas post-natal nutrient restriction may have a relatively protective effect.…”

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation

“…We developed a rat model of early, severe, and permanent food restriction and studied the impact on glucose homeostasis in females (14,15). The undernourished animals were exposed for 6.5 months to standard chow or to a cafeteria diet containing ϳ25% calories from fats, a formula that is less rich in lipids than those usually labeled as high-fat diets.…”

Growth restriction in the rat alters expression of metabolic genes during postnatal cardiac development in a sex-specific manner

“…The influence of growth restriction following uteroplacental insufficiency on the expression of these key cardiac glucose transporters during development is unknown. Importantly, adult female rats exposed to maternal and postnatal undernutrition have lower adult cardiac GLUT-1 and GLUT-4 gene expression (9), which may result in an impaired ability for energy provision from glucose during critical periods, such as ischemia.…”